Tiotropium bromide (compound of formula I, wherein R4 is methyl and X− is bromide) is a long-acting anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD).

Many syntheses have been recently developed to prepare the compound of formula I: Starting from natural scopolamine hydrobromide scopine and scopine methobromide (compound of formula V) have been prepared. The second building block di(2-thienyl)glycolate is readily available via addition of 2-magnesium or lithium thiophene to oxalic acid or esters thereof. Although syntheses of both building blocks have been sufficiently resolved the coupling of both fragments, scopine or scopine methobromide with di(2-thienyl)glycolate, is still too complex comprising too many steps and low overall yield.
As disclosed in U.S. Pat. No. 5,610,163 Tiotropium bromide was synthesized via N-demethylated Tiotropium which was obtained by a reaction of methyl di(2-thienyl)glycolate and scopine using sodium metal in melt or sodium hydroxide in melt. This method is definitely not suitable for an industrial preparation. The following quarternization of N-desmethyl tiotropium was carried out in a mixture of acetonitrile and methylenechloride using methyl bromide. The scopine used for this reaction sequence was prepared first time by reduction of scopolamine using NaBH4.
In U.S. Pat. No. 6,486,321 Tiotropium bromide has been prepared via tropenol derivatives involving even an additional epoxidation step.
US2006/0047120 reports another approach, direct coupling of scopine methobromide with trimethylsilyl protected sodium dithienyl glycolate prepared in situ.
US2008/0051582 discloses an improved original process using N-demethyl tiotropium in which the purity of the scopine salt should be crucial for preparative yield of the coupling reaction.
It is obvious that there is still a need for a better and more cost efficient method for coupling reaction of these two building blocks. No synthesis of Tiotropium bromide has ever been reported using a new cyclic anhydride of formula II which allows a very efficient coupling of both building blocks in high preparative yield and high purity.